Description Antigens expressed in the liver frequently lead to T cell inactivation, resulting in failure to eliminate the antigen. This is termed liver tolerance, was first described in the context of allogeneic liver transplants, but also accounts for the failure to eliminate liver pathogens including viruses and parasites. Based on published work and new Preliminary Data, we propose a unifying model which we term Adaptive Liver Tolerance. Our central Premise is that Adaptive Liver Tolerance explains immune failure in the liver. this model, hepatocellular antigens are presented directly to CD8+ T cells, but cross-presentation by bone marrow-derived APCs does not occur. Thus, hepatocellular antigens can engage CD4+ T cells only through cross-presentation by MHC-II+ tissue cells, for which the strongest candidates are liver sinusoidal endothelial cells. However, our data show that liver sinusoidal endothelial cells strongly up- regulate multiple immunosuppressive molecules. Therefore, the limited options for the cross- presentation of hepatocellular antigens leads to CD4+ T cell tolerance, and thus to CD8+ T cell exhaustion due to the lack of CD4+ T cell help. The immunosuppressive molecules that are expressed on liver sinusoidal endothelial cells are IFN-gamma responsive. Therefore, in this project we will (1) overcome the inactivation of CD4+ T cells, and test the prediction that this will reverse CD8+ T cell dysfunction; (2) directly test the hypothesis that IFN-gamma acting on the liver sinusoidal endothelial cells is the driver of the expression of immunosuppressive molecules, and of functional tolerance. These experiments use an optimized model of immunity to an extrinsic hepatocellular antigen delivered via an AAV vector, so we will also (3) test the applicability of the Adaptive Liver Tolerance model in a mouse model of chronic HBV infection. If the hypothesis is supported, it will be rational to target liver sinusoidal endothelial cells to promote tolerance in autoimmunity, and to break tolerance in chronic infection. It will further suggest that, in some circumstances, inhibition of IFN-gamma will usefully enhance immunity in the liver.